1. Field of the Invention
The invention relates to Isochroman-alkyl-piperazinyl-aryl compounds useful as anti-psychotic agents.
2. Description of the Related Art
Chromans (also known as 1-benzopyrans, where the oxygen atom is attached to the aromatic ring) and isochromans (also known as 2-benzopyrans, where the oxygen atom is not attached to the aromatic ring) are known in the art, as are aryl-piperazines (or aminopiperidines). Chromans and aryl piperazines linked together with an alkyl chain are also known. European Patent 300,908 discloses (1-benzopyran)!-alkyl-(piperazinyl or aminopiperidine)-aryls useful as antiarrythmics and anti-fibrillatory agents. The compounds of this invention require -alkyl-piperazinyl (or aminopiperidinyl)-aryl at carbon 1 of an 2- benzopyran ring which are useful for CNS and cardiovascular disorders.
Various isochromans, thioisochromans, benzoxepines, and benzothiepines with hydroxy, alkoxy, or o-methylenedioxy substitution on their aromatic rings, and linked to aryl piperazines(piperidines) by alkyl chains are known. These compounds are disclosed as being useful as antipsychotics and hypotensives. The compounds of this invention do not permit oxygen substitution on the aromatic ring of the isochroman, thioisochroman, benzoxepin, or benzothiepin ring system for their usefulness in CNS and cardiovascular disorders.
Another group of isochromans, thioisochromans, benzoxepines and benzothiepines with hydroxy, alkoxy, or o-methylenedioxy functionality attached to their aromatic rings, and linked to aryl piperazines(piperidines) by alkyl chains are known, useful as antipsychotics and hypotensives. The compounds of this invention do not permit oxygen substitution on the aromatic ring of the isochroman, thioisochroman, benzoxepin, or benzothiepin ring system for their usefulness in CNS and cardiovascular disorders.
U.S. Pat. No. 4,179,510 and the many divisionals thereof discloses isochromanalkyl-piperazinyl (or aminopiperidinyl)-aryls requiring oxygen as a substituent on the isochroman aromatic ring. These compounds are disclosed as being useful as hypotensive and antipsychotic agents.
Also disclosed are isochroman-, isothiochroman-, 2-benzoxepin-, and -2-benzothiepin-alkyloxyethanols as being useful for preparing the above compounds. More specifically 7,8-dimethoxybenzoxepines are disclosed as are 1-(6,7-dimethoxyisochroman)alkyl!-4-(aryl)piperazines. Further disclosed are 2-benzoxepine-alkyl-piperazine(aminopiperidine)-aryls, 2-benzothiepins and 2-benzoxepines all requiring an oxygen atom as a substituent on the aromatic ring and useful for the same purposes.
Dutch Patent 8,001,981 discloses 1-(2-chlorophenyl)-4-2-(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-y l)ethyl!piperazine useful as an antipsychotic agent.
International Patent Publication WO 9218089 discloses isochroman-alkyl-piperazinyl (aminopiperidinyl)-aryls, with the requirement that oxygen be present on the aromatic ring of the isochroman which are useful in sensitizing cells against multi-drug resistance.
International Patent Publication WO 8808424 discloses isochromans-alkyl-piperazinyl (or aminopiperidinyl)-aryls, with the requirement that oxygen be present on the aromatic ring of the isochroman, useful in the treatment of head injury, spinal trauma, and stroke.
International Patent Publication WO 9015056 and U.S. Pat. No. 5,140,040 disclose isochromans, tetralins, and dihydroanaphthalenes substituted with various alkyl amines for the treatment of glaucoma, depression, hypertension, congestive heart failure and vascular spastic conditions.
U.S. Pat. No. 4,994,486 discloses isochroman-alkyl-amines for treating psychoses, Parkinson's disease, and addictive behavior.
Japanese Patent 61083180 discloses isochroman-alkyl-(alkyl)amines as antiulcer agents.
European Patent 404,197 discloses isochroman-alkyl-piperazine-alkyl-keto (alcohol)-aryls with bronchodilator and antiallergy activity.
Japanese Patent 51125287 (J 52083846) discloses isochroman-alkyl-amines(piperazine) with antidepressive, analgesic, diuretic, antiinflammatory, and anti-asthma activity.
German Patent DE 2,624,693 and Great Britain Patent GB 1552004 discloses isochroman-alkyl-amines including aryl piperazines as analgesics, hypotensives, antidepressants, diuretics, antiinflammatories, muscle relaxants, and vasodilators. The compounds differ from the compounds of this invention in that oxygen substitution is required on the isochroman aromatic ring.
Japanese Patent 57159713 discloses isochroman- and tetralin-(no alkyl spacer)-piperazine-aryls as antiallergics. The compounds of this invention require at least one carbon as a linker.
U.S. Pat. Nos. 3,549,656 and 3,467,675 and Belgium Patent 678,035 disclose phthalan-, isochroman-, and isochromen-alkylene-amines for the treatment of depression.
European Patent 458,387 and U.S. Pat. No. 5,137,911 disclose isochroman-alkylene-piperazine-alkylene-aryls useful as blood platelet aggregation inhibitors, as intracellular calcium antagonists, and for treating cardiac dysrhythmias, angina pectoris, stroke, and myocardial infarction.
German Patent DE 3,409,612 discloses dimethoxyisochroman- and benzoxepine-alkyl-amino-alkyls for prophylaxis of coronary heart disease or hypertension.
Japanese Patent 6 1083180 discloses isochroman-alkyl-amines useful for treating ulcers. European Patent 457,686 discloses phthalan and indane alkyl aminopiperidinyl ureas or carbamates for the treatment of stress, pain, and schizophrenia.
Similar compounds include the indanes, indenes, tetralins, dihydronaphthalenes, benzocycloheptanes, benzocycloheptenes. European Patent 494,817 discloses indane-, tetralin-, and benzocycloheptane-alkyl-piperazine-benzisoxazoles and -benzothiazoles as dopamine and serotonin antagonists for the treatment of pain, depression, anxiety, psychosis, and schizophrenia. European Patent 428,437 discloses indane-alkyl-piperidine-benzisoxazoles for the treatment of schizophrenia and depression. European Patent 490,772 discloses tetralin(dihydronaphthalene)-alkyl-piperazine-aryls for the treatment of anxiety, depression, migraine, stress, and diabetes. The aryl group attached to piperazine must have an oxygen-containing ring fused to the benzene ring. U.S. Pat. No. 4,130,646 discloses tetralin-, dihydronaphthalene-, indane-, indene- substituted at the 2-position with -methylene-piperazine-aryl, as tranquillizers with sedative, muscle relaxant, and neuroleptic activity. AU 9180251 discloses tetralin- and dihydronapthalen-alkyl (or alkene)-piperidine(or pyrrolidine, tetrahydropyridine)-alkyl(alkylphenyl) useful for treating stress, hypertension, migraine, anxiety, depression, schizophrenia, and pain. Pol. J. Pharmacol. Pharm., 36(6), 697-703 (1984) discloses indane-alkyl-piperazine-phenyl where phenyl is optionally meta-substituted with chlorine, having serotoninolytic properties.
J. Med. Chem., 25(1), 75-81 (1982) discloses 6,7-dimethoxyisochroman-alkyl-piperazinyl-aryl type compounds which have hypotensive activity.
U.S. Pat. Nos. 5,032,598 and 5,215,989 generically encompass the isochromans and tetralins of the present invention if the variable substituents are appropriately chosen.
International Publication No. WO 88/08424 and U.S. Pat. No. 5,120,843 disclose a dialkoxyisochroman containing a substituted pyridinylpiperazinylethyl side chain. However, the compounds of the present invention do not permit alkoxy substitution. TO AVOID U-79,129
International Publication No. WO 94/00441 discloses tetralins containing a substituted aryl or heteroarylpiperazinyl side chain with an alkyl linker where the alkyl linker contains three or four carbon atoms, having serotoninergic, dopaminergic and adrenergic activity. The compounds of the present invention have less than three carbon atoms in the alkyl linking group. Further, there is no disclosure of any type of isochroman type compounds.
J. Med. Chem., 37, 99-104 (1994) discloses dihydronaphthalene-propyl-aryl piperazines with mixed serotonergic and dopaminergic activity. The compounds of the present invention have a two carbon linker.
Collection Czechoslov. Chem. Commun., 43, 1760-77 (1978) discloses tetralins which have a piperazinyl group attached directly to the tetralin moiety whereas the claimed compounds do not permit the piperazinyl group to be directly attached to the tetralin.
International Patent Publication No. WO 93/16057 discloses tetralins in which the piperazinyl substituent is attached directly to the tetralin which is not permitted in the claimed invention. This document discloses chromans but not isochromans.
U.S. Pat. No. 3,146,235 discloses a ketone on the tetralin portion of the molecule; the claimed compounds do not have this substitution. In addition, U.S. Pat. No. 3,146,235 discloses a 1-carbon linker between the tetralin and the nitrogen of the piperazine portion of the molecule; the claimed compounds disclose a 2-carbon linker.
Czechosolvican Patant 193,303 discloses compounds with no carbon linker between the tetralin and the nitrogen of the piperazine portion of the molecules, whereas the claimed compounds have a two carbon linker. The compounds of Czech. 193,303 are useful as antimicrobials, the claimed compounds are useful for CNS (schizophrenia, etc.) and cardiovascular diseases (fibrillation and arrhythmias).
Great Britain patent 1,434,854 discloses monocyclic heterocyclics containing sulfur (specifically thiophene) attached by a carbon linker of one to four carbons to one nitrogen of a piperazine ring; the second nitrogen of the piperazine ring is attached by a carbon linker of one to four carbons to an aryl group. The present invention discloses only bicyclic heterocyclics (with or without sulfur), linked to the first nitrogen of a piperazine ring by a two carbon linker and a direct attachment (no carbon linker) between the second nitrogen of the piperazine ring and an aryl group.
It has long been known that strong bases can induce racemization at chiral centers adjacent (.alpha.-position) to carbonyl compounds by deprotonation followed by protonation, the chiral center racemized in LVI is not adjacent to the carbonyl, but rather it is the .beta.-position.